Barry Dixon

The association of blood transfusion with mortality after cardiac surgery: cause or confounding? (CME)

BACKGROUND: Bleeding into the chest is a life‐threatening complication of cardiac surgery. Blood transfusion has been implicated as an important cause of harm associated with bleeding, based largely on studies demonstrating an independent association between transfusion and mortality. These studies did not, however, consider the possibility that bleeding may in itself be harmful, inasmuch as drains are inefficient at clearing blood from the chest and retained blood may compromise cardiac and lung function.

A phase 1 trial of nebulised heparin in acute lung injury

IntroductionAnimal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI.MethodsAn open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose.ResultsNo serious adverse events occurred for any dose. The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses.ConclusionAdministration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects.Trial registrationAustralian Clinical trials registry ACTRN12606000388516.

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

IntroductionProlonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.MethodsFifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.ResultsNebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.ConclusionsNebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.Trial registrationThe Australian Clinical Trials Registry (ACTR-12608000121369).

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

BackgroundData from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.MethodWe performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.ResultsThe efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.ConclusionLocal anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury.

BACKGROUND Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. METHODS Male Sprague-Dawley rats were intravenously challenged with lipopolysaccharide (LPS) and treated with nebulized normal saline (placebo), recombinant human-activated protein C (APC), plasma-derived antithrombin (AT), heparin, or danaparoid. RESULTS Intravenous administration of LPS resulted in lung injury associated with elevated bronchoalveolar levels of thrombin-antithrombin complex (TATc), 6.9 +/- 0.8 ng/mL (placebo) versus 0.5 +/- 0.2 ng/mL (healthy control) (p < 0.01), and elevated bronchoalveolar levels of fibrin degradation products (FDP), 555 +/- 74 ng/mL versus 27 +/- 12 ng/mL (p < 0.01). Nebulized APC, AT, and danaparoid all significantly limited the rise of bronchoalveolar levels of TATc, 2.4 +/- 0.7 ng/mL), 1.5 +/- 0.2, 3.8 +/- 0.7, and 3.2 +/- 0.9 ng/mL, respectively (all p < 0.01 vs. placebo), and fibrin degradation products, 243 +/- 77, 113 +/- 20, 317 +/- 74, and 300 +/- 42 ng/mL (all p < 0.01 vs. placebo). Heparin and danaparoid also significantly affected systemic coagulopathy. However, pulmonary inflammatory responses [neutrophil influx into the lungs, bronchoalveolar levels of myeloperoxidase, and bronchoalveolar levels of tumor necrosis factor (TNF), interleukin (IL)-6 and CINC-3], and histopathology of lungs were not affected by nebulization of anticoagulants. CONCLUSIONS In conclusion, local treatment with APC, AT, heparin, or danaparoid attenuate pulmonary coagulopathy, but not inflammation, in rats with endotoxemia-induced lung injury.

The Operating Surgeon Is an Independent Predictor of Chest Tube Drainage Following Cardiac Surgery

OBJECTIVES Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. DESIGN Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. SETTING Tertiary hospital. PARTICIPANTS Two thousand five hundred seventy-five patients. INTERVENTIONS Cardiac surgery. RESULTS The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. CONCLUSIONS The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes.

Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury

Previously in this journal, we published a phase 1 study of nebulized heparin in patients with acute lung injury [1]. Patients were administered heparin at doses of 50,000, 100,000, 200,000, or 400,000 U/day for 2 days, and bronchoalveolar lavage (BAL) fluid samples were taken at baseline and after the last heparin dose. The study demonstrated a trend to reduced coagulation activation (prothrombin fragments) in BAL fluid after the last dose of nebulized heparin [1]. Following publication of these data, we were offered the possibility of further analysis of the BAL fluid with additional markers of coagulation activation, including thrombin-antithrombin complexes (TATcs), fibrin degradation products (FDPs), and plasminogen activator activity (PAI-1) levels. We wish to publish the results of this further analysis. The 400,000 U/day group had one patient more than the same group in the previously published data. We found that TATc and FDP levels were significantly reduced in patients treated with 400,000 U/day of nebulized heparin, but not PAI-1 (Figure ​(Figure11 overleaf). We believe that these data are important as they demonstrate for the first time that nebulized heparin significantly reduces coagulation activation in the lungs of critically ill patients with acute lung injury. This may be important knowledge as inflammatory mechanisms related to coagulation activation, such as hyaline membrane formation and microvascular thrombosis, may mediate lung injury [2,3]. Figure 1 Changes in markers of coagulation activation in bronchoalveolar fluid before and after 2 days of nebulized heparin. Each line represents a single patient (*P < 0.01, **P < 0.001, paired t test). FDP, fibrin degradation product; NS, not ...

Plasminogen activator inhibitor activity is associated with raised lactate levels after cardiac surgery with cardiopulmonary bypass

ObjectiveTo investigate the pathophysiology underlying raised lactate levels after cardiac surgery with cardiopulmonary bypass (CPB). DesignProspective observational study. SettingMedical and surgical intensive care unit of a tertiary hospital. PatientsA total of 40 patients undergoing first-time coronary artery bypass grafting with CPB. InterventionsThe prothrombotic response to cardiac surgery with CPB was assessed by measuring plasma levels of prothrombin fragment 1 + 2 and plasminogen activator inhibitor (PAI) activity. The hemodynamic responses to cardiac surgery with CPB were also measured using standard techniques. Measurements and Main ResultsAfter cardiac surgery, prothrombin fragment 1 + 2 levels increased 6-fold and PAI activity increase 2- to 3-fold (p < .0001). Lactate levels were not associated with prothrombin fragment 1 + 2 and PAI activity levels after CPB. Lactate levels were associated with baseline PAI activity (p = .006), a history of hypertension (p = .02), raised baseline lactate levels (p = .02), an early increase in body temperature after CPB (p = .05), a late increase in oxygen consumption after CPB (p = .03), and a raised white cell count after CPB (p = .06). Lactate levels were inversely associated with the maximum activated clotting time level reached during CPB (p = .02). Multivariate linear regression demonstrated lactate levels were independently associated with baseline PAI activity. ConclusionWe found cardiac surgery with CPB was associated with a marked prothrombotic response. Lactate levels were associated with elevated baseline PAI activity and evidence of an amplified inflammatory response to cardiac surgery with CPB. Our findings implicate aspects of the inflammatory response, including microvascular thrombosis, in the development of raised lactate levels after cardiac surgery with CPB.

Nebulized fibrinolytic agents improve pulmonary fibrinolysis but not inflammation in rat models of direct and indirect acute lung injury.

Background Critically ill patients frequently develop acute lung injury (ALI). Disturbed alveolar fibrin turnover, a characteristic feature of ALI, is the result of both activation of coagulation and inhibition of fibrinolysis. Nebulized fibrinolytic agents could exert lung–protective effects, via promotion of fibrinolysis as well as anti–inflammation. Methods Rats were challenged intratracheally with Pseudomonas aeruginosa, resulting in pneumonia as a model for direct ALI, or received an intravenous bolus infusion of lipopolysaccharide, as a model for indirect ALI. Rats were randomized to nebulization of normal saline (placebo), recombinant tissue plasminogen activator (rtPA), or monoclonal antibodies against plasminogen activator inhibitor–type 1 (anti–PAI–1). Results Nebulized rtPA or anti–PA1–1 enhanced the bronchoalveolar fibrinolytic system, as reflected by a significant reduction of PAI–1 activity levels in bronchoalveolar lavage fluid, and a consequent increase in plasminogen activator activity (PAA) levels to supranormal values. Both treatments also significantly affected systemic fibrinolysis as reflected by a significant increase in PAA levels in plasma to supranormal levels. Neither nebulized rtPA nor anti–PA1–1 affected pulmonary inflammation. Neither treatment affected bacterial clearance of P. aeruginosa from the lungs in case of pneumonia. Conclusions Local treatment with rtPA or anti–PA1–1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats.

Pre-operative heparin reduces pulmonary microvascular fibrin deposition following cardiac surgery.

Cardiac surgery triggers a pulmonary inflammatory response due to lung ischemia and the release of inflammatory mediators through contact of bloodwith the foreign surface of the cardiopulmonary bypass circuit. There is indirect evidence that this inflammatory response may cause lung injury through the developmentof pulmonarymicrovascular fibrin deposition. Animal models of cardiopulmonary bypass or pulmonary ischemia demonstrated the development of pulmonary microvascular fibrin deposition. Furthermore, of important clinical relevance, administration of anti-coagulants limited both pulmonary microvascular fibrin deposition and the extent of lung injury [1–4]. Similar results have been demonstrated in clinical studies. Cardiac surgerywas associatedwith an increase in the pulmonary dead space (a finding consistentwith pulmonarymicrovascularfibrin deposition) and evidence of coagulation activation in the pulmonary circulation, providing strong but indirect evidence of pulmonary microvascular fibrin deposition [5]. Moreover, a pre-operative heparin infusion attenuated the increase in pulmonary dead space and the extent of coagulation activation in the pulmonary circulation [5]. In the current study we sought to establish direct evidence of pulmonary microvascular fibrin deposition in patients undergoing routine cardiac surgery through histological examination of a lung biopsy. In addition, we assessed if prophylactic anti-coagulation with heparin limited the extent of pulmonary microvascular fibrin deposition.